We found a match
Your institution may have access to this item. Find your institution then sign in to continue.
- Title
Intracellular lipid metabolism impairs β cell compensation during diet-induced obesity.
- Authors
Risheng Ye; Gordillo, Ruth; Mengle Shao; Toshiharu Onodera; Zhe Chen; Shiuhwei Chen; Xiaoli Lin; SoRelle, Jeffrey A.; Xiaohong Li; Miao Tang; Keller, Mark P.; Kuliawat, Regina; Attie, Alan D.; Gupta, Rana K.; Holland, William L.; Beutler, Bruce; Herz, Joachim; Scherer, Philipp E.; Ye, Risheng; Shao, Mengle
- Abstract
The compensatory proliferation of insulin-producing β cells is critical to maintaining glucose homeostasis at the early stage of type 2 diabetes. Failure of β cells to proliferate results in hyperglycemia and insulin dependence in patients. To understand the effect of the interplay between β cell compensation and lipid metabolism upon obesity and peripheral insulin resistance, we eliminated LDL receptor-related protein 1 (LRP1), a pleiotropic mediator of cholesterol, insulin, energy metabolism, and other cellular processes, in β cells. Upon high-fat diet exposure, LRP1 ablation significantly impaired insulin secretion and proliferation of β cells. The diminished insulin signaling was partly contributed to by the hypersensitivity to glucose-induced, Ca2+-dependent activation of Erk and the mTORC1 effector p85 S6K1. Surprisingly, in LRP1-deficient islets, lipotoxic sphingolipids were mitigated by improved lipid metabolism, mediated at least in part by the master transcriptional regulator PPARγ2. Acute overexpression of PPARγ2 in β cells impaired insulin signaling and insulin secretion. Elimination of Apbb2, a functional regulator of LRP1 cytoplasmic domain, also impaired β cell function in a similar fashion. In summary, our results uncover the double-edged effects of intracellular lipid metabolism on β cell function and viability in obesity and type 2 diabetes and highlight LRP1 as an essential regulator of these processes.
- Subjects
LIPID metabolism; ENDOENZYMES; OBESITY; CELL proliferation; HOMEOSTASIS; TYPE 2 diabetes; HYPERGLYCEMIA; INSULIN absorption &; adsorption
- Publication
Journal of Clinical Investigation, 2018, Vol 128, Issue 3, p1178
- ISSN
0021-9738
- Publication type
journal article
- DOI
10.1172/JCI97702